Despite the overall national success in reducing infant mortality rate in Ethiopia, infant mortality rate is still high in northwest Amhara region. This study is conducted in one of the high mortality areas with the aim of identifying risk factors that are associated with infant mortality in Northwest Amhara Region, Ethiopia. A prospective open cohort study involving 1752 infants (1472.4518 person years of follow-up) was undertaken from November 2009 to August 2011. Kaplan-Meier Survival analysis was used to estimate infant mortality rate. Risk factors associated with infant mortality were assessed using multivariate Poisson regression. The overall infant mortality rate was 88 per 1000 person-years (95% CI: 74.3, 104.9). After controlling other important predictors in multivariate Poisson regression, infants not exclusively breastfed [IRR?=?7.86, 95% CI: (5.11, 12.10), )], breast milk initiated after 24 hours of birth [IRR?=?4.84,95% CI: (2.94,7.99)], mothers not washing hands with soap after visiting toilet and before feeding child [IRR?=?4.61, 95% CI: (2.24, 9.48)], being rural residents [IRR?=?2.33, 95% CI: (1.12, 4.88)], infants born within 24 months for the previous birth [IRR?=?2.79, 95%CI: (1.88, 4.15)], have increased the risk of infant mortality. In conclusion, exclusive breast feeding is the strongest predictor of infant survival in this predominantly rural setting where hygienic standards are poor. Supporting mothers to exclusively breast feeding which is cost effective, safe and feasible strategy, can help reduce infant mortality in the study setting.